DESCRIPTION: It has been the long term goal of this research program to examine and understand the biological and molecular factors which regulate growth and tumorigenic progression of early stages of mouse mammary tumorigenesis. One class of early lesions, the alveolar hyperplasias, has been extensively described and forms the basis for the proposed experiments. In this grant renewal, the PI proposes to examine the role of cyclin D2 in growth regulation of mammary preneoplasias. Recent experiments have demonstrated that cyclin D2 is preferentially bound to cdk4 in mammary preneoplasias. The applicant has presented the hypothesis that cyclin D2 may act to inhibit cdk4 kinase activity in contrast to the activating effect of cyclin D1. Specific aim 1 examines the significance of cyclin D2 expression by 1) comparing cyclin D2 and its associated proteins in mammary populations of different tumorigenic potential after modulation by hormones; 2) examining the consequences of overexpression of cyclin D2 targeted to the mammary gland; and 3)modulating cyclin D2 by the growth inhibitor, hexamethylene bisacetamide. Specific aim 2 examines the role of p15/16INK and p27 proteins in preneoplastic cell growth by both protein analysis and overpression experiments. These experiments will increase the understanding of regulation of the growth and tumorigenic progression of mammary preneoplasias and provide a model system for understanding regulation of growth in early stage breast cancer.